LANOXIN

LANOXIN (digoxin) is one of the cardiac (or digitalis) glycosides, a closely related group of drugs having in common specific effects on the myocardium. These drugs are found in a number of plants. Digoxin is extracted from the leaves of Digitalis lanata . The term “digitalis” is used to designate the whole group of glycosides. The glycosides are composed of 2 portions: a sugar and a cardenolide (hence “glycosides”). Digoxin is described chemically as (3β,5β,12β)-3-[( O -2,6-dideoxy-β- D-ribo -hexopyranosyl-(1→4)- O -2,6-dideoxy-β- D-ribo -hexopyranosyl-(1→4)-2,6-dideoxy-β- D-ribo -hexopyranosyl)oxy]-12,14-dihydroxy-card-20(22)-enolide. Its molecular formula is C 41 H 64 O 14 , its molecular weight is 780.95, and its structural formula is: Digoxin exists as odorless white crystals that melt with decomposition above 230°C. The drug is practically insoluble in water and in ether; slightly soluble in diluted (50%) alcohol and in chloroform; and freely soluble in pyridine. LANOXIN Injection and Injection Pediatric are sterile solutions of digoxin for intravenous or intramuscular injection. The vehicle contains 42.5% (W/V) propylene glycol and 10% alcohol (V/V). The injection is buffered to a pH of 6.8-7.2 with 0.17% dibasic sodium phosphate and 0.08% anhydrous citric acid. Each 2-mL single-dose ampule or vial of LANOXIN Injection contains 500 mcg digoxin (250 mcg/mL). Dilution is not required. Each 1-mL single-dose ampule or vial of LANOXIN Injection Pediatric contains 100 mcg digoxin (100 mcg/mL). Dilution is not required. Digoxin Chemical Structure

LANOXIN is a cardiac glycoside indicated for: Treatment of mild to moderate heart failure in adults. ( 1.1 ) Increasing myocardial contractility in pediatric patients with heart failure. ( 1.2 ) Control of resting ventricular rate in adults with chronic atrial fibrillation. ( 1.3 ) 1.1 Heart Failure in Adults LANOXIN is indicated for the treatment of mild to moderate heart failure in adults. LANOXIN increases left ventricular ejection fraction and improves heart failure symptoms, as evidenced by improved exercise capacity and decreased heart failure-related hospitalizations and emergency care, while having no effect on mortality. Where possible, LANOXIN should be used in combination with a diuretic and an angiotensin-converting enzyme (ACE) inhibitor. 1.2 Heart Failure in Pediatric Patients LANOXIN increases myocardial contractility in pediatric patients with heart failure. 1.3 Atrial Fibrillation in Adults LANOXIN is indicated for the control of ventricular response rate in adult patients with chronic atrial fibrillation.

LANOXIN dose is based on patient-specific factors (age, lean body weight, renal function, etc.). See full prescribing information. Monitor for toxicity and therapeutic effect. ( 2 ) Intravenous administration is preferable to intramuscular. Avoid bolus administration. ( 2 ) 2.1 Important Dosing and Administration Information In selecting a LANOXIN dosing regimen, it is important to consider factors that affect digoxin blood levels (e.g., body weight, age, renal function, concomitant drugs) since toxic levels of digoxin are only slightly higher than therapeutic levels. Dosing can be either initiated with a loading dose followed by maintenance dosing if rapid titration is desired or initiated with maintenance dosing without a loading dose. Parenteral administration of digoxin should be used only when the need for rapid digitalization is urgent or when the drug cannot be taken orally. Intramuscular injection can lead to severe pain at the injection site, thus intravenous administration is preferred. If the drug must be administered by the intramuscular route, it should be injected deep into the muscle followed by massage. For adults, no more than 500 mcg of LANOXIN Injection should be injected into a single site. For pediatric patients, no more than 200 mcg of LANOXIN Injection Pediatric should be injected into a single site. Administer the dose over a period of 5 minutes or longer and avoid bolus administration to prevent systemic and coronary vasoconstriction. Mixing of LANOXIN Injection and Injection Pediatric with other drugs in the same container or simultaneous administration in the same intravenous line is not recommended. LANOXIN Injection and Injection Pediatric can be administered undiluted or diluted with a 4-fold or greater volume of Sterile Water for Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose Injection. The use of less than a 4-fold volume of diluent could lead to precipitation of the digoxin. Immediate use of the diluted product is recommended. Consider interruption or reduction in LANOXIN dose prior to electrical cardioversion [see Warnings and Precautions ( 5.4 )]. Discard unused portion of LANOXIN Injection and LANOXIN Injection Pediatric. 2.2 Loading Dosing Regimen in Adults and Pediatric Patients Table 1. Recommended LANOXIN Injection Loading Dose mcg = microgram Age Total IV Loading Dose (mcg/kg) Administer half the total loading dose initially, then ¼ the loading dose every 6-8 hours twice Premature 15-25 Full-Term 20-30 1-24 Months 30-50 2-5 Years 25-35 5-10 Years 15-30 Adults and pediatric patients over 10 years 8-12 2.3 Maintenance Dosing in Adults and Pediatric Patients Over 10 Years Old The maintenance dose is based on lean body weight, renal function, age, and concomitant products [see Clinical Pharmacology ( 12.3 )] . The recommended starting maintenance doses in adults and pediatric patients over 10 years old with normal renal function are given in Table 2 . Doses may be increased every 2 weeks according to clinical response, serum drug levels, and toxicity. Table 2. Recommended Starting LANOXIN Injection Maintenance Dosage in Adults and Pediatric Patients Over 10 Years Old mcg = microgram Age Total Intravenous Maintenance Dose, mcg/kg/day (given once daily) Adults and pediatric patients over 10 years 2.4-3.6 Table 3 provides the recommended (once daily) maintenance dose for adults and pediatric patients over 10 years old (to be given once daily) according to lean body weight and renal function. The doses are based on studies in adult patients with heart failure. Alternatively, the maintenance dose may be estimated by the following formula (peak body stores lost each day through elimination): Total Maintenance Dose = Loading Dose (i.e., Peak Body Stores) x % Daily Loss/100 (% Daily Loss = 14 + Creatinine clearance/5) Reduce the dose of LANOXIN in patients whose lean weight is an abnormally small fraction of their total body mass because of obesity or edema. Table 3. Recommended Maintenance Dose (in micrograms given once daily) of LANOXIN Injection in Pediatric Patients Over 10 Years Old and Adults by Lean Body Weight and by Renal Function a For adults , creatinine clearance was corrected to 70-kg body weight or 1.73 m 2 body surface area. If only serum creatinine concentrations (Scr) are available, a corrected Ccr may be estimated in men as (140 – Age)/Scr. For women, this result should be multiplied by 0.85. For pediatric patients, the modified Schwartz equation may be used. The formula is based on height in cm and Scr in mg/dL where k is a constant. Ccr is corrected to 1.73 m 2 body surface area. During the first year of life, the value of k is 0.33 for pre-term babies and 0.45 for term infants. The k is 0.55 for pediatric patients and adolescent girls and 0.7 for adolescent boys. GFR (mL/min/1.73 m 2 ) = (k x Height)/Scr b If no loading dose administered c The doses listed assume average body composition. Corrected Creatinine Clearance a Lean Body Weight c Number of Days Before Steady State Achieved b kg 40 50 60 70 80 90 100 10 mL/min 64 80 96 112 128 144 160 19 20 mL/min 72 90 108 126 144 162 180 16 30 mL/min 80 100 120 140 160 180 200 14 40 mL/min 88 110 132 154 176 198 220 13 50 mL/min 96 120 144 168 192 216 240 12 60 mL/min 104 130 156 182 208 234 260 11 70 mL/min 112 140 168 196 224 252 280 10 80 mL/min 120 150 180 210 240 270 300 9 90 mL/min 128 160 192 224 256 288 320 8 100 mL/min 136 170 204 238 272 306 340 7 2.4 Maintenance Dosing in Pediatric Patients Less Than 10 Years Old The starting maintenance dose for heart failure in pediatric patients less than 10 years old is based on lean body weight, renal function, age, and concomitant products [see Clinical Pharmacology ( 12.3 )] . The recommended starting maintenance doses for pediatric patients are given in Table 4 . These recommendations assume the presence of normal renal function. Table 4. Recommended Starting LANOXIN Injection Maintenance Dosage in Pediatric Patients Less Than 10 Years Old mcg = microgram Age Dose Regimen, mcg/kg/dose (given TWICE daily) Premature 1.9-3.1 Full-Term 3-4.5 1-24 Months 4.5-7.5 2-5 Years 3.8-5.3 5-10 Years 2.3-4.5 Table 5 provides average daily maintenance dose requirements for pediatric patients less than 10 years old (to be given twice daily) with heart failure based on age, lean body weight, and renal function. Table 5. Recommended Maintenance Dose (in micrograms given TWICE daily) of LANOXIN Injection in Pediatric Patients Less Than 10 Years of Age a Based upon Lean Body Weight and Renal Function a a Recommended are doses to be given twice daily. b The modified Schwartz equation may be used to estimate creatinine clearance. See footnote a under Table 3 . c If no loading dose administered. Corrected Creatinine Clearance b Lean Body Weight Number of Days Before Steady State Achieved c kg 5 10 20 30 40 50 60 10 mL/min 8 16 32 48 64 80 96 19 20 mL/min 9 18 36 54 72 90 108 16 30 mL/min 10 20 40 60 80 100 120 14 40 mL/min 11 22 44 66 88 110 132 13 50 mL/min 12 24 48 72 96 120 144 12 60 mL/min 13 26 52 78 104 130 156 11 70 mL/min 14 28 56 84 112 140 168 10 80 mL/min 15 30 60 90 120 150 180 9 90 mL/min 16 32 64 96 128 160 192 8 100 mL/min 17 34 68 102 136 170 204 7 2.5 Monitoring to Assess Safety, Efficacy, and Therapeutic Blood Levels Monitor for signs and symptoms of digoxin toxicity and clinical response. Adjust dose based on toxicity, efficacy, and blood levels. Serum digoxin levels less than 0.5 ng/mL have been associated with diminished efficacy, while levels above 2 ng/mL have been associated with increased toxicity without increased benefit. Interpret the serum digoxin concentration in the overall clinical context, and do not use an isolated measurement of serum digoxin concentration as the basis for increasing or decreasing the LANOXIN dose. Serum digoxin concentrations may be falsely elevated by endogenous digoxin-like substances [see Drug Interactions ( 7.4 )] . If the assay is sensitive to these substances, consider obtaining a baseline digoxin level before starting LANOXIN and correct post-treatment values by the reported baseline level. Obtain serum digoxin concentrations just before the next scheduled LANOXIN dose or at least 6 hours after the last dose. The digoxin concentration is likely to be 10-25% lower when sampled right before the next dose (24 hours after dosing) compared to sampling 8 hours after dosing (using once-daily dosing). However, there will be only minor differences in digoxin concentrations using twice daily dosing whether sampling is done at 8 or 12 hours after a dose. 2.6 Switching from Intravenous Digoxin to Oral Digoxin When switching from intravenous to oral digoxin formulations, make allowances for differences in bioavailability when calculating maintenance dosages (see Table 6 ). Table 6. Comparison of the Systemic Availability and Equivalent Doses of Oral and Intravenous LANOXIN Absolute Bioavailability Equivalent Doses (mcg) LANOXIN Tablets 60-80% 62.5 125 250 500 LANOXIN Intravenous Injection 100% 50 100 200 400

LANOXIN is contraindicated in patients with: Ventricular fibrillation [see Warnings and Precautions ( 5.1 )] Known hypersensitivity to digoxin (reactions seen include unexplained rash, swelling of the mouth, lips or throat or a difficulty in breathing). A hypersensitivity reaction to other digitalis preparations usually constitutes a contraindication to digoxin. Ventricular fibrillation. ( 4 ) Known hypersensitivity to digoxin or other forms of digitalis. ( 4 )

The following adverse reactions are included in more detail in the Warnings and Precautions section of the label: Cardiac arrhythmias [see Warnings and Precautions ( 5.1 , 5.2 )] Digoxin Toxicity [see Warnings and Precautions ( 5.3 )] The overall incidence of adverse reactions with digoxin has been reported as 5-20%, with 15-20% of adverse events considered serious. Cardiac toxicity accounts for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse events. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Covis Pharma at 1-877-411-2510 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In general, the adverse reactions of LANOXIN are dose-dependent and occur at doses higher than those needed to achieve a therapeutic effect. Hence, adverse reactions are less common when LANOXIN is used within the recommended dose range, is maintained within the therapeutic serum concentration range, and when there is careful attention to concurrent medications and conditions. In the DIG trial (a trial investigating the effect of digoxin on mortality and morbidity in patients with heart failure), the incidence of hospitalization for suspected digoxin toxicity was 2% in patients taking LANOXIN compared to 0.9% in patients taking placebo [see Clinical Studies ( 14.1 )] . The overall incidence of adverse reactions with digoxin has been reported as 5-20%, with 15-20% of adverse events considered serious. Cardiac toxicity accounts for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse events. Gastrointestinal: In addition to nausea and vomiting, the use of digoxin has been associated with abdominal pain, intestinal ischemia, and hemorrhagic necrosis of the intestines. CNS: Digoxin can cause headache, weakness, dizziness, apathy, confusion, and mental disturbances (such as anxiety, depression, delirium, and hallucination). Other: Gynecomastia has been occasionally observed following the prolonged use of digoxin. Thrombocytopenia and maculopapular rash and other skin reactions have been rarely observed.

Digoxin has a narrow therapeutic index, increased monitoring of serum digoxin concentrations and for potential signs and symptoms of clinical toxicity is necessary when initiating, adjusting, or discontinuing drugs that may interact with digoxin. Prescribers should consult the prescribing information of any drug which is co-prescribed with digoxin for potential drug interaction information. PGP Inducers/Inhibitors: Drugs that induce or inhibit PGP have the potential to alter digoxin pharmacokinetics. ( 7.1 ) The potential for drug-drug interactions must be considered prior to and during drug therapy. See full prescribing information. ( 7.2 , 7.3 , 12.3 ) 7.1 P-Glycoprotein (PGP) Inducers/Inhibitors Digoxin is a substrate of P-glycoprotein, at the level of intestinal absorption, renal tubular section and biliary-intestinal secretion. Therefore, drugs that induce/ inhibit P-glycoprotein have the potential to alter digoxin pharmacokinetics. 7.2 Pharmacokinetic Drug Interactions Pharmacokinetic interactions have been observed and reported primarily when digoxin is co-administered by oral route. There are very few studies that have evaluated the drug interaction when digoxin is administered via IV route. The magnitude of digoxin exposure change through IV route is generally lower than that through oral route. Table below provides available interaction data using digoxin IV formulation (NA means not available). Digoxin concentrations increased greater than 50% Digoxin Serum Concentration Increase Digoxin AUC Increase Recommendations Quinidine NA 54-83% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring. Ritonavir NA 86% Digoxin concentrations increased less than 50% Amiodarone 17% 40% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. Propafenone 28% 29% Quinine NA 34-38% Spironolactone NA 44% Verapamil NA 24% Mirabegron 29% 27% 7.3 Potentially Significant Pharmacodynamic Drug Interactions Because of considerable variability of pharmacodynamic interactions, the dosage of digoxin should be individualized when patients receive these medications concurrently. Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors may impair the excretion of digoxin. Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes. Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin. Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin. Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium. Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin. Sympathomimetics Epinephrine Norepinephrine Dopamine Can increase the risk of cardiac arrhythmias. Neuromuscular Blocking Agents Succinylcholine May cause sudden extrusion of potassium from muscle cells, causing arrhythmias in patients taking digoxin. Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients. Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block. Ivabradine Can increase the risk of bradycardia. 7.4 Drug/Laboratory Test Interactions Endogenous substances of unknown composition (digoxin-like immunoreactive substances [DLIS]) can interfere with standard radioimmunoassays for digoxin. The interference most often causes results to be falsely positive or falsely elevated, but sometimes it causes results to be falsely reduced. Some assays are more subject to these failings than others. Several LC/MS/MS methods are available that may provide less susceptibility to DLIS interference. DLIS are present in up to half of all neonates and in varying percentages of pregnant women, patients with hypertrophic cardiomyopathy, patients with renal or hepatic dysfunction, and other patients who are volume-expanded for any reason. The measured levels of DLIS (as digoxin equivalents) are usually low (0.2-0.4 ng/mL), but sometimes they reach levels that would be considered therapeutic or even toxic. In some assays, spironolactone, canrenone, and potassium canrenoate may be falsely detected as digoxin, at levels up to 0.5 ng/mL. Some traditional Chinese and Ayurvedic medicine substances like Chan Su, Siberian Ginseng, Asian Ginseng, Ashwagandha, or Danshen can cause similar interference. Spironolactone and DLIS are much more extensively protein-bound than digoxin. As a result, assays of free digoxin levels in protein-free ultrafiltrate (which tend to be about 25% less than total levels, consistent with the usual extent of protein binding) are less affected by spironolactone or DLIS. It should be noted that ultrafiltration does not solve all interference problems with alternative medicines. The use of an LC/MS/MS method may be the better option according to the good results it provides, especially in terms of specificity and limit of quantization.